WO2005102315A1 - Formulations de lactone synthetique pour maitrise la douleur - Google Patents

Formulations de lactone synthetique pour maitrise la douleur Download PDF

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Publication number
WO2005102315A1
WO2005102315A1 PCT/US2005/013098 US2005013098W WO2005102315A1 WO 2005102315 A1 WO2005102315 A1 WO 2005102315A1 US 2005013098 W US2005013098 W US 2005013098W WO 2005102315 A1 WO2005102315 A1 WO 2005102315A1
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substituted
compound
cancer
group
cyclic
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PCT/US2005/013098
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English (en)
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Federico M. Gomez
Federico C. Gomez Garcia-Godoy
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Magnachem International Laboratories, Inc.
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Publication of WO2005102315A1 publication Critical patent/WO2005102315A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present inventions are generally in the fields of pharmaceutically active lactones, their pharmaceutical formulations, and methods of use for treating pain.
  • Cross Reference to Related Applications This application claims benefit under 35 U.S.C. ⁇ 119 to U.S.
  • the lactone compound can be administered as the free base or a pharmaceutically acceptable salt or hydrate thereof.
  • these compounds are useful as anti-bacterial, anti-fungal and anti-inflammatory agents, and for treating proliferation disorders such as melanoma, leukemia, breast cancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer, liver cancer, and lymphatic cancer, as well as for treating pain associated with these disorders.
  • Patients report that they are able to be removed from morphine when treated with the compounds disclosed herein, especially alpha-methylene-gamma- butyrolactone.
  • Lactone Compositions A. Lactones. Lactones and their respective derivatives with a hydroxyl in the gamma position are disclosed.
  • lactones and the derivatives thereof can be synthesized or isolated from natural sources.
  • the lactones and the derivatives can be isolated by means of chromatographic methods, from a plant whose taxonomic scientific name is Securidaca virgata, which belongs to the botanical family Polygalaceae.
  • derivatives refers to any compounds that are made from the lactones by reacting the lactones with one or more chemical reagents.
  • the term also refers to any products obtainable by ring opening of the lactones with an organic or inorganic nucleophilic agents to form, for example, an acid, ester, amide, or any other products thereof.
  • the lactone has the following chemical structure:
  • R ⁇ -R.6 taken independently are a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic groupings containing any number of carbon atoms, preferably 1 - 8 carbon atoms, and optionally include a heteroatom such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats, representative Ri-R ⁇ groupings being H, alkyl, substituted alkyl, allyl, substituted allyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, alloxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio
  • R1-R4 taken independently may be a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic groupings containing any number of carbon atoms, preferably 1 - 8 carbon atoms, and optionally include a heteroatom such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats, representative R1-R4 groupings being H, alkyl, substituted alkyl, allyl, substituted allyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, alloxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthi
  • R1-R4 taken independently may be a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic groupings containing any number of carbon atoms, preferably 1 - 8 carbon atoms, and optionally include a heteroatom such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats, representative R1-R4 groupings being alkyl, allyl, substituted alkyl, alkenyl, allyl, substituted allyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, alloxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, aryl
  • the pharmaceutically acceptable acid addition salts of compounds of the formula la, lb, or Ic may be prepared in a conventional manner by treating a solution or suspension of the free base of the formula 1 with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques can be employed to isolate the salt.
  • the pharmaceutically acceptable base addition salts of compounds of formula 1 containing an acid group may be prepared in a conventional manner from the acid, e.g. by reaction with about one chemical equivalent of a base.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, ste
  • the pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.
  • lactone and functional derivatives can be formulated using standard techniques for enteral, parenteral, topical administration (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., John Wiley & Sons, Inc., New York, 1999). Effective dosages can be determined based on the in vitro assays known to those skilled in the art, such as the assays described in the examples.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Suitable pharmaceutically acceptable vehicles for parenteral delivery include sterile saline, phosphate buffered saline, apyrogenic sterile vehicle, and standard microparticulate formulations for injection, including polymeric microspheres, microcapsules, liposomes, and emulsions. These can include degradable polymers such as polylactic acid and polyglycolic acid, and copolymers thereof, polyanhydrides, polyorthoesters, and polyhydroxyalkanoates.
  • Suitable pharmaceutically acceptable carriers include talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non- aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.
  • the lactones will typically be formulated as solutions or suspensions in a liquid carrier.
  • the lactone may be formulated in an ointment, creams, lotion, gel, spray, or controlled or sustained release formulation (such as a transdermal patch).
  • the lactone may be formulated in a tablet, capsule, granule, suppository, suspension or- solution, dissolved or encapsulated in an excipient such as a sugar like lactose, inert compound such as magnesium stearate, paraffin derivatives, glycols or gum arabic.
  • the formulations may further include dyes, flavorings, preservatives, dispersing or emulsifying agents, or materials modifying release or stability properties of the formulations.
  • Formulations are prepared using a pharmaceutically acceptable "carrier” composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
  • the "carrier” is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • carrier includes but is not limited to diluents, binders, lubricants, desintegrators, fillers, and coating compositions. "Carrier” also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.
  • the delayed release dosage formulations may be prepared as described in references such as "Pharmaceutical dosage form tablets", eds. Liberman et. al.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit ® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides. Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copo
  • Optional pharmaceutically acceptable excipients present in the drug- containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants.
  • Diluents also termed “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
  • Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
  • Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
  • Lubricants are used to facilitate tablet manufacture.
  • suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
  • Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).
  • Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, and ammonium salts of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer ® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.
  • the amount of active agent released in each dose will be a therapeutical ly effective amount.
  • the active compound may be used in combination with a second pharmaceutically acceptable antimicrobial agent such as nitroimidazole antibiotics, e.g.
  • tinidazole and metronidazole tetracyclines, e.g. tetracycline, doxycycline and minocycline; penicillins, e.g. amoxicillin and meziocillin; cephalosporins, e.g. cefaclor, cefadroxil, cephadrine, cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil, ceftazidime and cefatriaxone; carbapenems, e.g. imipenem and meropenem; aminoglycosides , e.g. paromomycin; macrolide antibiotics, e.g.
  • erythromycin clarithromycin and azithromycin
  • lincosamide antibiotics e.g. clindamycin
  • rifamycins e.g. rifampicin
  • nitrofurantoin Combinations of the compounds with a pharmaceutical acid-lowering agent may used in the treatment of acid-related disorders, such as acid pump inhibitors, e. g., omeprazole and lansoprazole, or H antagonists, e.g., ranitidine, cimetidine, and famotidine.
  • the synthesis of the lactones of formulae la, lb, and Ic involves: a) forming an intermediate or precursor having the lactone structure, and b) reacting the intermediate with one or more appropriate chemical agents to form the lactones of formulae la, lb, and Ic.
  • the method involves: a) providing a precursor having the following structure:
  • an acetylene can react with an aldehyde in the presence of a phosphine, [CH 3 (CH ) 3 ] 3 P, to form compound A, which undergoes a ring-rearrangement reaction to form compound B in enolic form.
  • a phosphine [CH 3 (CH ) 3 ] 3 P
  • Enolic compound B is in equilibrium with its ketone form, compound C.
  • Compound H can be readily derivatized to form compound I (Formula la) using, for example, an alkyl halide in the presence of a base such as sodium carbonate, sodium hydroxide, or sodium methoxide or ethoxide.
  • a base such as sodium carbonate, sodium hydroxide, or sodium methoxide or ethoxide.
  • More functionalized lactones can be prepared by readily available synthetic method in the art (see, for example, March, "Advanced Organic Chemistry," 4 th Edition, 1992, Wiley-Interscience Publication, New York).
  • the pharmaceutically acceptable salts of the lactone compounds of the Formulae Ia-c if in the form of an acid or a base such as an amine, can be prepared in a conventional manner by treating a solution or suspension of the compound of Formulae Ia-c with about one chemical equivalent of a pharmaceutically acceptable base or acid.
  • the lactones are useful to treat pain, particularly pain associated with disorders including cancers.
  • Representative types of cancers include melanoma, leukemia, breast cancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer, liver cancer, and lymphatic cancer.
  • the lactones can be formulated into analgesic compositions.
  • Analgesic compositions are comprised of a therapeutically effective amount of a compound of formulae la, lb, or Ic or a salt thereof and an inert pharmaceutical carrier to alleviate pain.
  • B. Dosages The effective amount will be determined based on the pain to be treated, the mode of administration and the formulation. Effective dosages can be routinely determined based on the effective dosages determined using in vivo assays such as those described in the examples.
  • the preferred compound is alpha-methylene-gamma-butyrolactone, also referred to as 4,5-dihydro-3-methylene-2[3H]furanone, "Securolide” or "LMSV-6", for the treatment of pain.
  • Typical doses for cancer patients for relief of pain are 60mg/day given once or twice daily intramuscularly.
  • the LD 50 in rabbits for the compounds disclosed is 225 mg kg.
  • Typical maximum dosages for humans is 60% of the LD 50 .
  • Toxicity in humans occurs between about 300 and 400 mg/day.
  • the compounds can be administered to humans for the treatment of pain associated with disorders such as cancer by either the oral or parenteral routes and may be administered orally at dosage levels of about 0.1 to about 100 mg/kg, advantageously about 0.5 to 60 mg/kg/day given once or twice a day.
  • dose levels are about 0.1 to about 100 mg/kg/day, preferably about 0.5 to about 60 mg/kg/day.
  • intramuscular administration may be a single dose or up to 4 divided doses
  • intravenous administration can include a continuous drip.
  • the lactone composition can be administered by any standard route, either systemically, topically or locally. Preferred routes of administration are by injection, orally using an enteric coating, or topically in ointment form. The mode of administration will vary with the type of pain to be alleviated.
  • the compounds may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • the compounds may be administered as syrup or enteric coated tablets.
  • they can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, sufficient salt or glucose to make the solution isotonic.
  • a preferred method of intramuscular administration of the alpha- methylene-gamma-butyrolactone is via an oil-based carrier, such as
  • Cremophor the same carrier typically used to administer taxol.
  • a more preferred method is via an injectable aqueous solution.
  • the compounds can be administered as a cream with a dose of 60 mg/12 g of an emulsion such as Vaseline®. Variations in dosage and formulation will result based on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art. The present invention will be further understood by reference to following non-limiting examples.
  • Example 1 Study of Adverse Reactions to LMSV-6 in Healthy Volunteers Methods Nineteen healthy volunteers participated in the study. The age of the participants was between 21 and 40 years with an average of 30.5 ⁇ 7.2 years.
  • the weight was between 150 and 190 pounds with a median of 163.2 ⁇ 14.3 pounds and the height was 1.8 to 2.1 meters with an average of 1.9 ⁇ 0.1 meters.
  • the subjects were selected at random in agreement with the national and international criteria and norms established for investigations with human beings.
  • the state of health of the participants was established using several clinical evaluations, laboratory tests, electrocardiographs and thoracic radiographs.
  • the functionality of the liver and the renal systems was verified by chemical-enzymatic studies.
  • tests of blood chemistry, pathology and urinalysis were carried out.
  • the absence of pregnancy and/or lactation was verified by means of laboratory tests and gynecological evaluation.
  • Group I placebo
  • Group II received 2.0 ml of saline solution (ClNa + , 0.9%)
  • Group II received 60mg of LMSV-6 intramuscularly
  • Group III received 100 mg of LMSV-6 intramuscularly.
  • the respiratory frequency (FR) was maintained in a range of 18 to 20 respirations per minute during the entire test. According to that which was observed in the basal conditions and in the placebo group, none of the parameters evaluated dealing with the respiratory dynamic, inspiration, aspiration, tracheal respiration, bronchial respiration and thoracic-pulmonary distension and the superior and inferior airflow, suffered any alteration.
  • the evaluation of the effects of LMSV-6 with respect to the renal function parameters showed that the values of urinary frequency in individuals of the control group and those who were treated were maintained within a range, without much significant variation, of 3.1 ⁇ 0.7 to 3.3 ⁇ 1.5 times in a period of 12 hours of direct observation.
  • the average urinary volume in the same period was between 434.2 ⁇ 213.2, 489.2 ⁇ 94.3 and 394.3 ⁇ 103.9 ml in the placebo groups and the groups which received 60 and 100 mg of LMSV-6, respectively.
  • the data of the evaluation of the effects of LMSV-6 on cutaneous sensitivity and temperature indicate that the treatment did not provoke any change in the cutaneous sensitivity, or in the temperature of the participants.
  • Example 2 Administration to Cancer Patients Securolide was administered to a number of cancer patients for the treatment of cancer. The dosage was 60 mg/once or twice daily. The dosage was given in an oil base or in Cremophor by intramuscular injection. An unanticipated outcome of the study was that patients who were on morphine for control of pain were able to be removed from the morphine and were free from pain associated with the cancer.

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Abstract

L'invention concerne des composés naturels et synthétiques présentant une structure de lactone ainsi qu'un procédé permettant de soulager de la douleur, notamment la douleur associée à des troubles tels que le mélanome, la leucémie, le cancer du sein, le cancer du poumon, le cancer de l'ovaire, le cancer du côlon, le cancer de l'oesophage, le cancer du foie, le cancer lymphatique. Des études initiales ont démontré que les patients peuvent être sevrés de la morphine si, de préférence, on leur administre alpha-méthylène-gamma-butyrolactone en dose comprise entre 60 et 120 mg/jour par voie intramusculaire.
PCT/US2005/013098 2004-04-23 2005-04-18 Formulations de lactone synthetique pour maitrise la douleur WO2005102315A1 (fr)

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WO2008092084A2 (fr) * 2007-01-26 2008-07-31 Centocor, Inc. Suspension non aqueuse injectable présentant une concentration élevée en agent thérapeutique
KR100808490B1 (ko) 2007-04-20 2008-03-25 바이오스펙트럼 주식회사 에스-마이너스-튤리팔린비 또는아세틸화된-에스-마이너스-튤리팔린비를 함유하는 조성물
US20080293901A1 (en) * 2007-05-25 2008-11-27 Basf Corporation Polymers and compounds prepared with alpha-methylene lactones, methods therefor, and coatings
CN101820757A (zh) 2007-06-01 2010-09-01 普林斯顿大学托管委员会 通过调节宿主细胞代谢途径治疗病毒感染
KR101427092B1 (ko) * 2012-01-13 2014-08-07 제일모직주식회사 α-메틸렌락톤의 제조 방법

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US20050239877A1 (en) 2005-10-27
US8188145B2 (en) 2012-05-29
US8546444B2 (en) 2013-10-01
US20120231050A1 (en) 2012-09-13

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